Solid lipid nanoparticles: an oral bioavailability enhancer vehicle

Introduction: The therapeutic efficacy of perorally administered drugs is often obscured by their poor oral bioavailability (BA) and low metabolic stability in the gastrointestinal tract (GIT). Solid lipid nanoparticles (SLNs) have emerged as potential BA enhancer vehicles for various Class II, III and IV drug molecules.

Area covered: This review examines the recent advancements in SLN technology, with regards to oral drug delivery. The discussion critically examines the effect of various key constituents on SLN absorption and their applications in oral drug delivery. The relationship between the complexity of absorption (and various factors involved during absorption, including particle size), stability and the self-emulsifying ability of the lipids used has been explored.

Expert opinion: The protective effect of SLNs, coupled with their sustained/controlled release properties, prevents drugs/macromolecules from premature degradation and improves their stability in the GIT. An extensive literature survey reveals that direct peroral administration of SLNs improves the BA of drugs by 2- to 25-fold. Overall, the ease of large-scale production, avoidance of organic solvents and improvement of oral BA make SLNs a potential BA enhancer vehicle for various Class II, III and IV drugs.     

Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs

The purpose of this work was to improve the oral bioavailability of poorly soluble drugs by incorporation into solid lipid nanoparticles (SLNs). All-trans retinoic acid (ATRA) was used as a poorly soluble model drug. Different formulations of SLNs loaded with ATRA were successfully prepared by a high-pressure homogenization method and using Compritol 888 ATO as lipid matrix. The particle size and distribution, drug loading capacity, drug entrapment efficiency (EE %), zeta potential, and long-term physical stability of the SLNs were investigated in detail. Drug release from two sorts of ATRA-SLN was studied and compared with the diffusion from ATRA solution in 0.1 M HCl, distilled water and phosphate buffer (pH 7.40), using a dialysis bag method. A pharmacokinetic study was conducted in male rats after oral administration of 8 mg kg(-1) ATRA in different formulations and it was found that the relative bioavailability of ATRA in SLNs was significantly increased compared with that of an ATRA solution. The amount of surfactant also had a marked effect on the oral absorption of ATRA with SLN formulations. Although an emulsion formulation also increased ATRA absorption, it was too unstable for use in clinical situations. The absorption mechanism of the SLN formulations was discussed. These results indicate that ATRA absorption is enhanced significantly by employing SLN formulations. SLNs offer a new approach to improve the oral bioavailability of poorly soluble drugs.     

Solid lipid nanoparticles loading candesartan cilexetil enhance oral bioavailability: in vitro characteristics and absorption mechanism in rats

Candesartan cilexetil (CC) is widely used for the treatment of hypertension and heart failure, but it shows very poor aqueous solubility and very low oral absorption. In this work, CC-loaded solid lipid nanoparticles (CLNs) were successfully developed to improve the oral bioavailability. The physicochemical properties of CLNs were characterized, and the pharmacokinetic behavior of CLNs was evaluated in rats. CLNs exhibited nanometer-sized spherical particles with high entrapment efficiency (91.33%). The absorption of CLNs in the stomach was only 2.8% of that in intestine. Moreover, CLNs could be internalized into the enterocytes and then transported into the systemic circulation via the portal circulation and intestinal lymphatic pathway. The pharmacokinetic results indicated that the oral bioavailability of candesartan was obviously improved over 12-fold after incorporation into solid lipid nanoparticles. These results demonstrated that solid lipid nanoparticles have great potential for increasing oral bioavailability of lipophilic drugs such as CC. FROM THE CLINICAL EDITOR: Candesartan cilexetil is a potent angiotensin receptor inhibitor with low bioavailability due to poor aqueous solubility. In this work, solid lipid nanoparticles were used to improve the oral bioavailability 12-fold compared to standard preparation in rats, suggesting that a similar approach might be effective in future human applications.     

Solid lipid microparticles: An approach for improving oral bioavailability of aspirin

The objectives of the work were to develop a lipid based delivery system for aspirin and to evaluate its physicochemical and pharmacodynamic properties. Aspirin-loaded solid lipid microparticles (SLMs) were formulated by hot homogenization and analysed for their encapsulation efficiency (EE%), in vitro release, particle size, anti-inflammatory and ulcer inhibition properties. Particle size ranged from 33.10 ± 5.85 to 43.50 ± 7.27 µm for batches A1 to A3 SLMs loaded with 1, 3 and 5% aspirin and containing Poloxamer 407, while batches B1, B2 and B3 formulated with Soluplus as surfactant had particle size range of 31.10 ± 1.46 to 45.60 ± 2.92 µm. Batches A1 and B1 containing 1% of aspirin had the highest EE of 70 and 72% respectively. Maximum in vitro release of 95.1 and 93.2% were obtained at 8 h from batches A1 and B1 respectively. SLMs exhibited about 77.8% oedema inhibition, while the reference had 66.7% and ulcer inhibition range of 25–75%. Aspirin-loaded SLMs exhibited good properties and could be used orally twice daily for the treatment of inflammation.     

Solid lipid nanoparticles: a possible vehicle for zinc oxide and octocrylene

An efficient sunscreen formulation shows good absorption in the relevant UV range. Efficacy also means that the UV absorber must be easily incorporated in any kind of formulation. In this study, a chemical absorber, octocrylene, and one of the most important physical blockers, zinc oxide, could be successfully incorporated into Solid Lipid Nanoparticle (SLN) systems which themselves have UV blocking potential similar to physical sunscreens, and remained stable for a period of 360 days while providing UVA and UVB protection. Crystalline structure related to the chemical nature of the solid lipid is a key factor to decide whether a sunscreening agent will be expelled or incorporated in the long-term and for a controlled optimization of active ingredient incorporation and loading, intensive characterization of the physical state of the lipid particles was highly essential. Thus, FT-IR, NMR, XRD and DSC analyses were performed and the results did not indicate stability problems. pH values of the SLN systems were found to be between 5.4-5.9 in all formulations which may be buffered by the skin. Transpore test results proved the UV blocking potential of the SLNs with not any active ingredient and the synergistic effects by the incorporation of molecular sunscreens. Therefore, concentration of molecular sunscreens in the formulations was decreased to 0.6%. UVA and UVB screening potentials of octocrylene and zinc oxide formulations were compared in the 290-400 nm wavelength region. Zinc oxide loaded SLN suspensions were found to be more effective in the UVA region while octocrylene loaded ones performed better in the UVB region.     

Highly water-soluble mast cell stabiliser-encapsulated solid lipid nanoparticles with enhanced oral bioavailability

Cromolyn sodium (CS), a mast cell stabiliser, is widely employed for the prevention and treatment of allergic conditions. However, high hydrophilicity and poor oral permeability hinder its oral clinical translation. Here, solid lipid nanoparticles (SLNs) have been developed for the purpose of oral bioavailability enhancement. The CS–SLNs were engineered by double emulsification method (W₁/O/W₂) and optimised by using Box–Behnken experimental design. The surface and solid-state characterisations revealed the presence of CS in an amorphous form without any interactions inside the spherical-shaped SLNs. The in-vitro release study showed an extended release up to 24?hr by diffusion controlled process. Ex-vivo and in-vivo intestinal permeation study showed ～2.96-fold increase in permeability of CS by presentation as SLNs (p?<?0.05). Further, in-vivo pharmacokinetic study exhibited ～2.86-fold enhancements in oral bioavailability of CS by encapsulating inside SLNs, which clearly indicate that SLNs can serve as the potential therapeutic carrier system for oral delivery of CS.     

Effect of particle size on oral bioavailability of darunavir-loaded solid lipid nanoparticles

The present investigation aimed to study the effect of particle size of solid lipid nanoparticles (SLNs) on oral bioavailability of darunavir. High pressure homogenisation technique was used to prepare SLNs. Three different sized SLNs loaded with darunavir were developed with mean particle sizes of around 100?nm, 200?nm and 500?nm, respectively. The in vivo pharmacokinetics in rats showed a significant increase in oral bioavailability of darunavir from all the three formulations in comparison to plain drug suspension and reference tablet. The results revealed insignificant difference between SLNs of 100 and 200?nm and these had significantly higher bioavailability in comparison to SLNs of 500?nm. However, more number of homogenisation cycles is required for obtaining 100?nm and thus we selected 200?nm as an optimum size for oral bioavailability enhancement of darunavir. The optimised SLN formulation was stable for a period of 6 months at 25?±?2?°C/60?±?5% relative humidity (RH).     

Solid lipid nanoparticles as carriers for oral delivery of hydroxysafflor yellow A

Hydroxysafflor yellow A (HSYA) is the main bioactive flavonoid extracted from the flower of Carthamus tinctorius L., which is widely used in traditional Chinese medicine for the treatment of myocardial ischemia and cerebral ischemia. HSYA has high water solubility but poor intestinal membrane permeability, resulting in low oral bioavailability. Currently, only HSYA sodium chloride injection has been approved for clinical use and oral formulations are urgently needed. In this study, HSYA solid lipid nanoparticles (SLNs) with the structure of w/o/w were prepared by a warm microemulsion process using approved drug excipients for oral delivery to increase the oral absorption of HSYA. The optimized HSYA SLNs are spherical with an average size of 214 nm and the encapsulation efficiency is 55%. HSYA SLNs exhibited little cytotoxicity in Caco-2 and Hela cells, but increased the oral absorption of HSYA about 3.97-fold in rats, compared to HSYA water solution. In addition, cycloheximide pretreatment significantly decreased the oral absorption of HSYA delivered by SLNs. Importantly, the pharmacodynamics evaluation demonstrated that SLNs further decreased the infarct areas in rats. In conclude, SLNs could be a promising delivery system to enhance the oral absorption and pharmacological activities of HSYA.     

Pharmacokinetics,tissue distribution and relative bioavailability of geniposide-solid lipid nanoparticles following oral administration

Abstract

Geniposide has various pharmacological effects; however, low oral bioavailability limits its clinical utility. This study explores the pharmacokinetics, tissue distribution and relative bioavailability of geniposide-solid lipid nanoparticles (SLNs) following oral administration. The geniposide solution and geniposide-SLNs were orally administered to the rats, respectively. The C_max value of geniposide in the geniposide-SLNs was significantly higher than that obtained with geniposide solution. Compared with the geniposide solution, the t_1/2 and MRT were prolonged; the CL and V1/F were increased with geniposide-SLNs. The AUC_0–∞values of geniposide-SLNs were 50 times greater than geniposide solution. The ratios of AUC_{0–8 h} in the liver, spleen, heart, kidney, brain and lung of the geniposide-SLNs to geniposide solution were 25.93, 4.28, 27.91, 10.15, 5.16 and 16.22, respectively. Prepared geniposide-SLNs are very helpful for increasing the bioavailability of geniposide. These data suggest that SLNs are a promising delivery system to enhance the oral bioavailability of geniposide.     

Pharmacokinetics, tissue distribution and relative bioavailability of puerarin solid lipid nanoparticles following oral administration

Puerarin has various pharmacological effects; however, poor water-solubility and low oral bioavailability limit its clinical utility. A delivery system of solid lipid nanoparticles could enhance its oral absorption. The objective of this study was to investigate the pharmacokinetics, tissue distribution and relative bioavailability of puerarin in rats after a single dose intragastric administration of puerarin solid lipid nanoparticles (Pue-SLNs). The puerarin concentrations in plasma and tissues were determined by rapid resolution liquid chromatography electrospray ionization-tandem mass spectrometry. The C(max) value of puerarin after the administration of Pue-SLNs was significantly higher than that obtained with puerarin suspension (0.33±0.05 μg/mL vs. 0.16±0.06 μg/mL, P<0.01). The T(max) value after the administration of the Pue-SLNs was significantly shorter than that after puerarin suspension administration (40±0 min vs. 110±15.49 min, P<0.01). The AUC(0→t) values of puerarin were 0.80±0.23 mg h/L, and 2.48±0.30 mg h/L after administration of the puerarin suspension and Pue-SLNs, respectively. Following administration of the Pue-SLNs, tissue concentrations of puerarin also increased, especially in the target organs such as the heart and brain. These data suggest that SLNs are a promising delivery system to enhance the oral bioavailability of puerarin.     

Solid lipid nanoparticles incorporated in dextran hydrogels: a new drug delivery system for oral formulations

Solid lipid nanoparticles (SLN) containing or not (S)-(+)-2-(4-isobutylphenyl)propionic acid (ibuprofen) were prepared with Preciol ATO 5 as lipid phase by the hot homogenization technique and characterized through particle size analyses and zeta potential measurements. DSC experiments carried out on the freeze-dried samples of loaded SLN showed a shift of the melting endotherm of the lipid phase, with the maximum at a temperature value higher then that of the "empty" SLN. (1)H NMR of the nanosuspension allowed to calculate the encapsulation efficiency of the particles that was 52+/-3%. By adding dextran methacrylate (DEX-MA) to the aqueous phase and submitting the mixture to UV irradiation, systems of SLN (drug-loaded and unloaded) incorporated into a dextran hydrogel were prepared. Finally, dissolution studies of ibuprofen from the freeze-dried samples were performed. The comparison among the release profiles of ibuprofen from SLN, DEX-MA hydrogel and SLN/DEX-MA-hydrogel allows to affirm that this last system, retaining about 60% of the drug after 2h in acid medium and releasing it slowly in neutral solution, is suitable for modified delivery oral formulations.     

Solid lipid nanoparticles,an effective carrier for classical antifungal drugs

Solid-lipid nanoparticles (SLNs) are an innovative group of nanosystems used to deliver medicine to their respective targets with better efficiency and bioavailability in contrast to classical formulations. SLNs are less noxious, have fewer adverse effects, have more biocompatibility, and have easy biodegradability. Lipophilic, hydrophilic and hydrophobic drugs can be loaded into SLNs, to enhance their physical and chemical stability in critical environments. Certain antifungal agents used in different treatments are poorly soluble medications, biologicals, proteins etc. incorporated in SLNs to enhance their therapeutic outcome, increase their bioavailability and target specificity. SLNs-based antifungal agents are currently helpful against vicious drug-resistant fungal infections. This review covers the importance of SLNs in drug delivery of classical antifungal drugs, historical background, preparation, physicochemical characteristic, structure and sizes of SLNs, composition, drug entrapment efficacy, clinical evaluations and uses, challenges, antifungal drug resistance, strategies to overcome limitations, novel antifungal agents currently in clinical trials with special emphasis on fungal infections.     

Solid lipid nanoparticles: Production,characterization and applications

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.     

Solid lipid nanoparticles: production, characterization and applications

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.     

Solid lipid nanoparticles for ocular drug delivery

Ocular drug delivery remains challenging because of the complex nature and structure of the eye. Conventional systems, such as eye drops and ointments, are inefficient, whereas systemic administration requires high doses resulting in significant toxicity. There is a need to develop novel drug delivery carriers capable of increasing ocular bioavailability and decreasing both local and systemic cytotoxicity. Nanotechnology is expected to revolutionize ocular drug delivery. Many nano-structured systems have been employed for ocular drug delivery and yielded some promising results. Solid lipid nanoparticles (SLNs) have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids. SLNs are especially useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. SLNs have another advantage of allowing autoclave sterilization, a necessary step towards formulation of ocular preparations. This review outlines in detail the various production, characterization, sterilization, and stabilization techniques for SLNs. In-vitro and in-vivo methods to study the drug release profile of SLNs have been explained. Special attention has been given to the nature of lipids and surfactants commonly used for SLN production. A summary of previous studies involving the use of SLNs in ocular drug delivery is provided, along with a critical evaluation of SLNs as a potential ocular delivery system.     

Solid lipid nanoparticles for parenteral drug delivery

This review describes the use of nanoparticles based on solid lipids for the parenteral application of drugs. Firstly, different types of nanoparticles based on solid lipids such as "solid lipid nanoparticles" (SLN), "nanostructured lipid carriers" (NLC) and "lipid drug conjugate" (LDC) nanoparticles are introduced and structural differences are pointed out. Different production methods including the suitability for large scale production are described. Stability issues and drug incorporation mechanisms into the particles are discussed. In the second part, the biological activity of parenterally applied SLN and biopharmaceutical aspects such as pharmacokinetic profiles as well as toxicity aspects are reviewed.     

Solid lipid nanoparticles as drug delivery systems

For a decade, trials have been made to utilize solid lipid nanoparticles (SLNs) as alternative drug delivery systems to colloidal drug delivery systems such as lipid emulsions, liposomes, and polymeric nanoparticles. Various lipid matrices, surfactants, and other excipients used in formulation, preparation methods, sterilization and lyophilization of SLNs are discussed in this article. Entrapment efficiency of drug carrier and its effect on physical parameters, drug release, and release mechanisms of various compositions are reviewed and discussed. Important points in characterization and stability of SLNs are outlined. Various in vitro studies carried out by different research groups are mentioned in addition to in vivo evaluation. Exploitation potential of SLNs to administer by various routes of administration are covered. Passive and active drug targeting using SLNs are presented.     

Solid lipid nanoparticles for topical drug delivery

Solid lipid nanoparticles (SLN) have shown interesting potential as a drug delivery system for the topical delivery of various drugs. However, their performance when applied to the skin has not been fully investigated because of the complexity of their composition and structure. Theoretically, drug can be targeted systemically to the vasculature in the dermis, locally to the skin strata, or superficially to the surface of the skin. Therefore, the topical delivery vehicle should be designed according to the desired therapeutic purposes. To understand drug permeation behavior, it is essential to elucidate the pattern of drug release from the SLN formulations. A number of different drug release patterns have been outlined in the literature, and these patterns have been found to be related to the manufacturing process of the vehicle. In this paper, we summarize the results of SLN-mediated skin penetration data in the literature and illustrate several theoretical mechanisms of SLN-skin interactions that might take place at the site of action. Substantial research dedicated to the development of this promising drug delivery system is still required.     

Solid lipid nanoparticles and nanostructured lipid carriers--innovative generations of solid lipid carriers

The first generation of solid lipid carrier systems in nanometer range, Solid Lipid Nanoparticles (SLN), was introduced as an alternative to liposomes. SLN are aqueous colloidal dispersions, the matrix of which comprises of solid biodegradable lipids. SLN are manufactured by techniques like high pressure homogenization, solvent diffusion method etc. They exhibit major advantages such as modulated release, improved bioavailability, protection of chemically labile molecules like retinol, peptides from degradation, cost effective excipients, improved drug incorporation and wide application spectrum. However there are certain limitations associated with SLN, like limited drug loading capacity and drug expulsion during storage, which can be minimized by the next generation of solid lipids, Nanostructured lipid carriers (NLC). NLC are lipid particles with a controlled nanostructure that improves drug loading and firmly incorporates the drug during storage. Owing to their properties and advantages, SLN and NLC may find extensive application in topical drug delivery, oral and parenteral administration of cosmetic and pharmaceutical actives. Cosmeceuticals is emerging as the biggest application target of these carriers. Carrier systems like SLN and NLC were developed with a perspective to meet industrial needs like scale up, qualification and validation, simple technology, low cost etc. This paper reviews present status of SLN and NLC as carrier systems with special emphasis on their application in Cosmeceuticals; it also gives an overview about various manufacturing techniques of SLN and NLC.